1. Field of the Invention
The present invention relates to methods and compositions for the production of biocompatible polymers having improved biocompatibility properties. In particular, the invention relates to improved aliphatic hydrocarbon derivatized biocompatible polymers which are established on surfaces of articles adapted for use in contact with blood or blood products.
2. Description of the Related Art
In the past decade, much progress has been made in the development of biocompatible polymers for use in contact with blood or blood products. The general availability of a wide range of polymer types has allowed their implementation in a wide range of medical devices, including, for example, vascular graft tubings, dialysis tubings or membranes, blood bags, tissue prostheses, artificial organs, and the like. Unfortunately, in certain instances, particularly where the article is intended to remain in contact with blood or tissue for extended periods of time, such polymers tend to present various problems associated with physiological and chemical stability and compatability with respect to various contacted tissues and biological fluids.
Both bulk and surface properties determine the functional biocompatibility of the material. Mechanical strength, elasticity, flexibility, creep and fatigue resistance, chemical inertness, impermeability to water vapor, resistance to acid attack, etc. are desired bulk properties of many biomaterials which should be maintained in vivo. The surfaces of exogenous materials in contact with bodily tissues should desirably exhibit resistance to red and white thrombus formation (e.g. blood coagulation, platelet adhesion and aggregation) immunological attack, complement activation, cell adhesion, pannus formation, and the like. These undesirable properties which can result from blood and other tissue interacting with the surface may compromise the intended use of the biomaterial in certain medical devices, and quite possibly result in device failure.
Application of most non-physiologic biomaterials and prostheses to tissue contact initiates a series of physiologic events on the surface of such biomaterials. In particular, a biomaterial such as a synthetic polymer in contact with blood rapidly forms an adsorbed protein layer. Within seconds after application, the biomaterial interface is coated with a thin proteinaceous film, rich in fibrinogen, fibronectin and gamma globulin and other proteins. As blood circulates, further protein components contribute to the thickness of the film. Conformational alterations and complexing of proteins occur, activating defense mechanisms, e.g., coagulation, platelet adhesion and aggregation, white cell adhesion, complement activation etc.
A number of approaches to provide tissue compatibility and specifically blood thromboresistance have been proposed and many promising materials have been developed. However none of the biomaterials developed heretofore have been totally successful and most have provided a poor compromise between device function and long term compatibility.
One such approach has been to modify the surface of existing biomaterials in an effort to prevent endogenous protein adhesion and accumulation so as to avoid coagulation and cell adhesion. Surface modification techniques which have been evaluated for biocompatibility and functionality include low polarity surfaces, glow discharge treated surfaces, negatively charged surfaces, and surfaces coated with biological material, e.g. enzymes, heparin, endothelial cells, and proteins.
The low polarity surfaces such as silicone polymers, and hydrogels, were developed in the view that low surface free energy, specifically low interfacial energy would limit the driving potential for adhesion of proteins and cellular material. Although the silicone biomaterials are substantially chemically inert and improve blood compatibility, platelet aggregation and cell accumulation eventually result with blood contact, especially at low blood flow rates. Glow discharge treated surfaces have temporarily improved the patency of small diameter synthetic vascular grafts. There is no evidence, however, that the effect is of a duration of clinical significance.
Another approach to enhance thromboresistance was to provide materials having negatively charged surfaces. Electrets, hydrogels and negatively charged biological molecules such as heparin, exhibit this property and appear to have improved, but not provide complete thromboresistance. Hydrogels, water saturated polymeric gels exhibiting a net negative surface charge, offer high biological compatibility but by their very nature of high water content lack structural strength and durability.
The biological coated polymers are of considerable interest due to their variability and complexity. Proteinaceous material such as heparin, albumin, and streptokinase have all been covalently bound to polymeric surfaces to enhance thromboresistance. Albumin is of particular interest for a surface coating because of its apparent passivating activity.
Heretofore, albumin has been physically adsorbed, and electrostatically and covalently bound to polymer surfaces. While temporary and partial protection against thrombogenesis is obtained by these methods, the albumin coating is eventually denatured or lost. The loss of albumin functionality when passively adsorbed may be traced to competitive reactions with other proteins having higher affinities for the polymer surface, ablation of the adsorbed albumin, or conformational changes, and fragmentation. Furthermore covalently bound albumin is subject to internal masking by the polymer tertiary structure caused by long term reconstitution of the polymer surface. As the polymer undergoes tertiary reorganization new, unfilled binding sites are presented to which thrombogenic proteins may gain a "foothold".
A further approach which has been taken to improve the thromboresistance of biocompatible polymers is through the alkylation of the polymers with aliphatic hydrocarbon extensions. As shown in U.S. Pat. No. 4,530,974, the addition of aliphatic extensions to the surface of polymers provide thereon a hydrophobic binding site for albumin. Thus, when such articles are implemented with whole blood or blood products, they selectively enhance albumin affinity binding to the exclusion of other blood components, and subsequently minimize thrombus formation.
Unfortunately, the principal methods for hydrocarbon attachment known in the art relate primarily to the addition of hydrocarbon groups to de-protonated amino and imino functions, through the use of a proton abstracting base. This can sometimes present certain disadvantages. For example, the density and distribution of hydrocarbon groups on the resultant derivatized polymer can be limited where amino and/or imino functions are sparsely located within the polymeric structure. Moreover, where the amino and/or imino functions are sterically hindered, or simply unavailable, the polymer can generally not be derivatized in an effective manner.
Other derivatized biocompatible polymers of the prior art have suffered from additional problems, ranging from difficult if not tedious preparation conditions to problems of decreased biocompatibility over extended periods of time. The ideal aliphatic hydrocarbon-derivatized biopolymer exhibits properties of consistently high and "natural" albumin binding with a resultant low activation of coagulation, low complement activation, platelet or white cell adhesion. By "natural" albumin binding is meant binding wherein the aliphatic hydrocarbon-adsorbed albumin molecules tend to retain their natural conformation and hence do not become denatured as readily with time. This allows albumin-adsorbed surfaces to retain their improved surface properties for greatly extended periods of time.
There is currently a great need to provide polymeric surfaces which are biocompatible yet in which some or all of the disadvantages of prior art polymers have been addressed. In particular, there is a need to provide alternative methods for derivatization in the case of biocompatible polymers which contain few accessible amino or imino functions. It is further desirable that these polymer surfaces provide consistent biocompatibility in terms of thromboresistance, resistance to cell adhesion in general and resistance to immunological attack over a range of blood flow rates including status, pH, electrolyte conditions, and hematologic makeups such as anemia, polycythemia, and thrombocytemia.